Research and Applications of Human Liver Organoids: Progress and Developments

doi:10.13523/j.cb.2304008

China Biotechnology

2023, Vol. 43

Issue (8): 20-29 DOI: 10.13523/j.cb.2304008

Research and Applications of Human Liver Organoids: Progress and Developments

ZHU Xiang¹,ZHANG Jing-yin²,WANG Li-rui^3,^*(

)

1 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211112, China
2 Obstetrics and Gynecology Department, Zhongda Hospital Southeast University, Nanjing 210009, China
3 Institute of Modern Biology, Nanjing University, Nanjing 210008, China

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Abstract

The liver is the major metabolic organ in the body and it plays a crucial regulatory role in maintaining homeostasis. In recent years, liver diseases have seriously threatened human health. However, the in vitro cultured cell lines or in vivo animal models cannot thoroughly reveal pathogenesis of human liver diseases and explore potential therapeutic targets effectively. Human liver organoids (HLOs), which are cell clusters differentiated from human cells through 3D culture in vitro, can mimic the structures and functions of the human liver in vitro. HLOs provide a new model for understanding the physiological structures and functions of the liver, simulating liver diseases in vitro, and exploring drugs for liver disease treatment. This review summarizes establishment strategies and applications of HLO models in recent years, and also discusses the defects of these models, which aim to provide a theoretical basis for the clinical applications of HLOs.

Key words： Liver Liver diseases Human liver organoids Three dimensional culture

Received: 04 April 2023 Published: 05 September 2023

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Cite this article:

ZHU Xiang, ZHANG Jing-yin, WANG Li-rui. Research and Applications of Human Liver Organoids: Progress and Developments. China Biotechnology, 2023, 43(8): 20-29.

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https://manu60.magtech.com.cn/biotech/10.13523/j.cb.2304008 OR https://manu60.magtech.com.cn/biotech/Y2023/V43/I8/20

细胞名称	细胞因子		肝脏类器官特点		参考文献
人脐静脉内皮细胞、人间充质干细胞、人诱导肝脏内胚层细胞	激活素A、碱性成纤维细胞生长因子(bFGF)、骨形态发生蛋白4(BMP4)、抑瘤素M (OSM)		血管化的人肝芽组织		[24]
人肝内胆管上皮细胞	R-spondin1蛋白、表皮生长因子(EGF)、成纤维细胞生长因子10(FGF10)、肝细胞生长因子(HGF), 骨形态发生蛋白7(BMP7)、成纤维细胞生长因子19(FGF19)、胃泌素		外观呈规则囊泡状,且具有人肝实质细胞特征		[37]
人肝癌细胞	R-spondin1蛋白、Wnt3A蛋白、表皮生长因子(EGF)、成纤维细胞生长因子10(FGF10)、肝细胞生长因子(HGF)、Noggin蛋白、骨形态发生蛋白7(BMP7)、成纤维细胞生长因子19(FGF19)、胃泌素		致密球状或不规则囊泡状结构		[21]
人诱导性多能干细胞	激活素A、骨形态发生蛋白4(BMP4)、肝细胞生长因子(HGF)、表皮生长因子(EGF)、抑瘤素M (OSM)、成纤维细胞生长因子10(FGF10)		同时具有人肝实质细胞和胆管上皮细胞两种特征		[38]
人诱导性多能干细胞分化而来的间充质细胞、内皮细胞和肝向内胚层细胞	激活素A、Wnt3A蛋白、碱性成纤维细胞生长因子(bFGF)、骨形态发生蛋白4(BMP4)、血管内皮细胞生长因子(VEGF)、血小板衍生生长因子BB(PDGFBB)、成纤维细胞生长因子(FGF2)		血管化的人肝芽结构		[25]
人肝母细胞	R-spondin1蛋白、表皮生长因子(EGF)、肝细胞生长因子(HGF)、成纤维细胞生长因子7(FGF7)、成纤维细胞生长因子10(FGF10)、转化生长因子-α(TGF-α)、抑瘤素M (OSM)		呈葡萄串状,具有人肝实质细胞特征		[20]
人胚胎肝祖细胞	催乳素、表皮生长因子(EGF)、肝细胞生长因子(HGF)、抑瘤素M(OSM)		同时具有人肝实质细胞和胆管上皮细胞两种特征		[23]
人诱导性多能干细胞	激活素A、碱性成纤维细胞生长因子(bFGF)、肝细胞生长因子(HGF)、抑瘤素M(OSM)		在微流控系统内衍生而来,同时具有人肝实质细胞和胆管上皮细胞两种特征		[26]
人诱导性多能干细胞	胃泌素、表皮生长因子(EGF)、R-spondin1蛋白,成纤维细胞生长因子10(FGF10)、肝细胞生长因子(HGF)、Noggin蛋白、Wnt3A蛋白		同时具有人肝实质细胞和胆管上皮细胞两种特征		[39]
人胚胎干细胞、人诱导性多能干细胞	激活素A、骨形态发生蛋白4(BMP4)、成纤维细胞生长因子4(FGF4)、Noggin蛋白		同时具有人肝、胆、胰特征的人肝-胆-胰类器官		[31]
人胚胎干细胞、人诱导性多能干细胞	激活素A、骨形态发生蛋白4(BMP4)、成纤维细胞生长因子4(FGF4)、肝细胞生长因子(HGF)、抑瘤素M(OSM)		同时具有人肝实质细胞样细胞、人星状细胞样细胞和人库普弗样细胞		[27]
人胚胎干细胞	激活素A、Wnt3A蛋白、表皮生长因子(EGF)、成纤维细胞生长因子2(FGF2)、骨形态发生蛋白4(BMP4)、胃泌素、R-spondin1蛋白	呈规则囊泡状,具有向人肝实质细胞和胆管上皮细胞双向分化潜能		[28]
人诱导性多能干细胞	激活素A、骨形态发生蛋白4(BMP4)、成纤维细胞生长因子4(FGF4)、骨形态发生蛋白2(BMP2)、角质细胞生长因子(KGF)、抑瘤素M(OSM)	同时具有2D水平的人肝实质样细胞和3D水平的囊泡状胆管类器官的肝胆类器官		[29]
人胚胎干细胞、人诱导性多能干细胞	骨形态发生蛋白4(BMP4)、碱性成纤维细胞生长因子(bFGF)、表皮生长因子(EGF)、肝细胞生长因子(HGF)、成纤维细胞生长因子7(FGF7)、骨形态发生蛋白7(BMP7)、成纤维细胞生长因子19(FGF19)	同时具有人肝实质细胞和胆管上皮细胞特征,且具有功能性的胆管结构		[32]
人诱导性多能干细胞	激活素A、碱性成纤维细胞生长因子(bFGF)、肝细胞生长因子(HGF)、骨形态发生蛋白4(BMP4)、抑瘤素M(OSM)	在微流控系统内衍生而来,同时具有人肝实质细胞和胆管上皮细胞两种特征		[33]
人诱导性多能干细胞	激活素A、骨形态发生蛋白2(BMP2)、成纤维细胞生长因子4(FGF4)、肝细胞生长因子(HGF)、角质细胞生长因子(KGF)、胃泌素、表皮生长因子(EGF)、转化生长因子-α(TGF-α)、成纤维细胞生长因子7(FGF7)、成纤维细胞生长因子10(FGF10)、抑瘤素M(OSM)	具有人肝实质细胞特征		[35]
人肝内胆管上皮细胞	R-spondin1蛋白、表皮生长因子(EGF)、成纤维细胞生长因子10(FGF10)、肝细胞生长因子(HGF)、骨形态发生蛋白7(BMP7)、成纤维细胞生长因子19(FGF19)、胃泌素	呈规则囊泡状结构,具有人肝实质细胞特征		[35]
人胚胎干细胞、人诱导性多能干细胞	激活素A、骨形态发生蛋白4(BMP4)、成纤维细胞生长因子4(FGF4)、表皮生长因子(EGF)、血管内皮细胞生长因子(VEGF)、成纤维细胞生长因子2(FGF2)、肝细胞生长因子(HGF)、抑瘤素M(OSM)	同时具有人肝实质细胞样细胞、人星状细胞样细胞和人库普弗样细胞		[34,36]
人诱导性多能干细胞	激活素A、碱性成纤维细胞生长因子(bFGF)、肝细胞生长因子(HGF)、抑瘤素M(OSM)	在微流控系统内衍生而来,同时具有人肝实质细胞和胆管上皮细胞两种特征		[40]
人肝母细胞	肝细胞生长因子(HGF)、表皮生长因子(EGF)、胃泌素、成纤维细胞生长因子10(FGF10)、R-spondin1蛋白	呈规则囊泡状结构,具有人肝实质细胞特征		[41]

Table 1 The cells and growth factors used for establishing different HLOs

Fig.1 The establishment strategies of HLOs from human normal tissues The HLOs derived from adult or fetal livers requires the isolation of adult stem cells (ASCs) such as hepatic progenitor cells or intrahepatic biliary epithelial cells (IBECs), followed by 3D culture under specific conditions. HLOs derived from ASCs or IBECs contain single cell type which call for culture medium with complex compositions but simple differentiation process

Fig.2 The establishment strategies of HLOs from hPSCs Establishing HLOs from hPSCs is a complex process that involves various methods of differentiation, all of which require definitive endoderm differentiation towards the liver, followed by induction of maturation under specific conditions. HLOs derived from hPSCs possess diverse cell types and spatial structures, making them suitable for various experimental purposes


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